Chemotherapy and radiotherapy constitute common treatments for many diseases. Although such methods of therapy can be used effectively in the therapy of diseases such as cancer, exposure to biologically significant levels of radiation can also cause genotoxic stress. Similarly, many industrial processes (such as the production of nuclear power) and military uses (such as nuclear weapons) can expose individuals to hazardous levels of genotoxic agents. Such exposure can elicit a variety of cellular responses, ranging from cell-cycle arrest to mutation, malignant transformation, or cell death.
Due to individual genetic make-up, some people have defective DNA repair mechanisms, resulting in chromosome instability. There are three main consequences of such chromosome instability. These individuals may have (1) developmental abnormalities (birth defects), (2) predisposition to cancers, and (3) hypersensitivity of their tissues to radiation and chemotherapy.
In severe cases, such individuals may be born with an obvious genetic disease (i.e., Fanconi Anemia). This disease results from a complete knockout of both alleles of a particular DNA repair gene. In less severe and more common cases, individuals may have a partial disruption of a DNA repair gene or pathway. Such a disruption may result from inheriting a “variant” DNA repair gene, such as a single nucleotide polymorphism in a Fanconi Anemia (FA) gene. While these individuals may have normal development (i.e., no evidence of birth defects), the only clinical sequelae of their genetic weakness may be the early onset of cancer, or radiation or drug sensitivity. The identification of such individuals, before they develop cancer or before they develop life-threatening toxicity from radiation/drug exposure, is an important, unsolved problem in clinical medicine.
Predicting radiation/chemotherapy toxicity is difficult and relies, at present, on circumstantial evidence. First, individuals who have early onset of rare cancers or strong family histories of cancer, with clear autosomal dominant or recessive inheritance, may have an underlying genetic defect. In these cases, culprit cancer susceptibility genes (BRCA1, BRCA2, p53) can be sequenced to confirm or rule out the defect. Second, individuals who have subtle clinical findings, reminiscent of a more preformed genetic disease (i.e. skin cafe au lait spots or short stature), may have an underlying DNA repair disorder.
Efforts to predict which cancer patients have an underlying DNA repair disorder have been largely ineffectual. While FA patients and Blooms syndrome patients have obvious (measurable) defects in chromosome breakage, patients with more subtle DNA repair disorders do not score positive in typical chromosome breakage studies. Standard doses of radiation/chemotherapy are given to all cancer patients, depending on the specific tumor type and location. Approximately 2% of these patients may have unexpected severe toxic reactions, as the first evidence of their underlying DNA repair disorder.
There is a need in the art for a method of detecting exposure to a genotoxic agent in a live sample (i.e., a so-called biological dosimeter). There is also a need in the art for methods of testing an individual's sensitivity to a genotoxic agent. There is also a need in the art for a method of determining damage caused to an individual by exposure to a genotoxic agent. There also exists a need in the art for a method to identify agents which are active in modulating the responses of cells toward genotoxic agents. There also exists a considerable need to obtain compounds which are active in protecting an individual from probable exposure to a genotoxic agent such as radiation and genotoxic carcinogens.